Amputation of extremities leads to two common types of pain, phantom and stump pain. Phantom pain is a debilitating neuropathic pain syndrome that occurs in more than 50% of amputees. Presently available modalities for the management of this intractable, chronic pain state are unreliable and better therapies are necessary. Several pharmacological and non- pharmacological therapeutic regimens have been suggested for the treatment of phantom pain. However, none of the treatments have been shown, in controlled studies, to be effective in more than 30% of patients. The long-term objective of this proposal is to develop better pharmacological therapies for alleviating the pain and associated functional limitations of postamputation phantom pain. Specifically, we will assess whether chronic opioid or mexiletine therapy will significantly ameliorate pain and improve function in patients with phantom pain, monitoring carefully for treatment complications. A detailed psychiatric evaluation of patients will be conducted, using assessment tools with established validity in chronic illness and pain, to determine if the presence of lifetime and current prevalence of co- morbid psychiatric illness affects the outcome of treatment with morphine, mexiletine, or placebo. The effects of intravenous bolus infusions of lidocaine, morphine, and saline (placebo) on pain will be determined in a masked fashion on separate days prior to inclusion in the treatment trials with oral morphine or mexiletine. Patients (N=108) with persistent phantom pain 6 months after amputation will be enrolled in a randomized, double-blind, placebo-controlled, crossover study. After a drug-free baseline period, each patient will undergo 3 treatment periods: a placebo period and treatment periods with mexiletine and morphine. Each treatment period will consist of drug taper, drug titration (4 weeks), and maintenance treatment (2 weeks) phases. During the drug taper phase, any previous therapy will be tapered off, while during the titration phase the study drug will be titrated to maximal effect on pain. Patients will be randomized to 6 treatment groups to control for treatment and order effects. Outcome measures will assess impairment (pain intensity, pain relief, quantitative sensory tests), physical functioner disability, and psychosocial function or handicap. Measurements will be made before and at the end of each of the three treatment periods. The impact of any co-morbid illness on treatment and placebo response, and cognitive and/or affective complications of opioid and mexiletine therapy, will be evaluated. The study will also evaluate whether i.v. infusion tests can predict the success of subsequent oral therapy with the same drugs. Strengths of the study design include: 1) double-blind cross-over design that will allow within-subject comparisons of the efficacy of both mexiletine and morphine versus placebo and 2) controls for treatment and order effects. The proposed clinical studies are likely to answer the crucial question of the efficacy of opioid and mexiletine therapies in the management of phantom and associated neuropathic pain syndromes in amputees.